VENOUS THROMBOEMBOLISM: DURATION OF TREATMENT - Thrombosis Canada

[Pages:9]VENOUS THROMBOEMBOLISM: DURATION OF TREATMENT

OBJECTIVE:

To provide guidance on the recommended duration of anticoagulant therapy for venous thromboembolism (VTE).

BACKGROUND:

Determining the duration of anticoagulant therapy depends on the assessment of an individual's risk of recurrent thrombosis off anticoagulation versus the risk of major bleeding on anticoagulation. While case-fatality rates of recurrent VTE and major bleeding events are similar during the initial period of VTE treatment, the case fatality rate of recurrent VTE is lower after completion of 3 to 6 months of anticoagulation compared to that for major bleeding. This means that long-term therapy is not always associated with a net mortality benefit, especially in patients at lower risk of recurrent VTE or higher bleeding risk. There are unfortunately no long-term randomized studies comparing short term to indefinite anticoagulation duration.

Risk of VTE Recurrence

The risk of recurrent VTE after stopping anticoagulation appears to be similar whether anticoagulant therapy is stopped after 3 months vs. after 6 to 24 months of treatment. This suggests that 3 months of treatment is sufficient to treat the acute episode of VTE if the decision is to not continue anticoagulation long-term. Three months is the minimum duration of treatment for proximal deep vein thrombosis (DVT) or pulmonary embolism (PE) because shortening the duration of anticoagulation from 3 or 6 months to 4 or 6 weeks results in doubling of the frequency of recurrent VTE during the first 6 months after stopping anticoagulant therapy.

After 3 months, a decision must be made about whether to continue anticoagulation. This decision will depend on balancing the risk of recurrence (which depends mainly on whether the VTE was provoked by a transient risk factor, unprovoked, or related to a major persistent risk factor such as active cancer) and the risk of bleeding (see below).

Other considerations:

? Type of index event: the risk of VTE recurrence is similar after an episode of proximal DVT versus PE. However, patients who presented initially with PE are more likely to recur with PE than DVT, while those who present initially with DVT are more likely to recur with DVT. The risk of recurrence appears lower (by 50%) after an isolated calf (distal) DVT than after a proximal DVT or PE.

? Burden of anticoagulation (financial, functional, and psychological), and quality of life

? Patient preference: anticoagulant therapy should be stopped when its benefits no longer clearly outweigh its risks or, when patients who have a good understanding of the associated risks, want to stop even if continuing treatment is expected to be of net benefit.

? 2021 Thrombosis Canada

Page 1 of 9

Bleeding Risk Estimation

The risk of anticoagulant-induced bleeding varies markedly among patients and must be balanced against the benefits of continuing anticoagulation. The risk of anticoagulant-induced bleeding is highest during the first 3 months of treatment and stabilizes after the first year.

Unfortunately, we do not currently have adequately validated bleeding risk tools to provide accurate estimates of bleeding risk in patients with VTE. Bleeding risk scores such as HASBLED were derived in patients with atrial fibrillation (AF), who generally have higher baseline bleeding risk, so major bleeding*estimates from these studies may not apply to patients on anticoagulation for VTE prevention who have already completed 3 to 6 months of therapy.

One approach is to identify variables that appear to be predictors of bleeding in multiple studies in both AF and VTE, to form an overall impression of bleeding risk (see Table 1). Patients with two or more such risk factors may be considered to be at least moderate bleeding risk. One should carefully consider whether extended anticoagulant therapy is warranted in such individuals.

TABLE 1: BLEEDING RISK FACTORS

? Age > 70 ? Active cancer ? Anemia ? Antiplatelet therapy ? Chronic kidney disease ? Chronic liver disease ? Prior history of bleeding ? Thrombocytopenia

There is suggestion that long term use of direct oral anticoagulants (DOACs) (as opposed to warfarin) may provide a better safety profile in terms of major bleeding. In patients who have completed 6 months of anticoagulant therapy, the rate of major bleeding with DOACs approximates the major bleeding risk associated with ASA while having a superior efficacy in terms of reduction in recurrent VTE.

PATIENTS WITH VTE PROVOKED BY A TRANSIENT RISK FACTOR:

Patients with VTE provoked by a transient risk factor (Table 2) in the 3 months prior to the event have a much lower risk of recurrence than those with an unprovoked VTE or a persistent risk factor. Patients with VTE provoked by a transient risk factor which has resolved should generally receive only 3 months of anticoagulation. However, 6 months may be preferred if: (i) the DVT or PE was

* Major bleeding is variably defined in studies, but contemporary studies usually define it as bleeding that is fatal, occurs in a critical organ/space, results in a reduction of hemoglobin of at least 20 g/L, and/or results in the transfusion of at least 2 units of blood.

? 2021 Thrombosis Canada

Page 2 of 9

very large or very symptomatic; or (ii) symptoms of the initial DVT or PE persist; or (iii) the patient is not ready (confident enough) to stop anticoagulant therapy at 3 months; and (iv) the patient does not have a high risk for bleeding.

TABLE 2: EXAMPLES OF TRANSIENT VTE RISK FACTORS

CATEGORY OF

TRANSIENT RISK FACTOR Major

Minor

EXAMPLES OF RISK FACTORS

? Surgery with general anesthetic for 30 minutes ? Admission to hospital for an acute illness with confinement to

bed for at least 3 days ? Surgery with general anesthetic for 8

hours, medical illness with immobilization)

15%

*The risk of recurrence in women with a first VTE associated with estrogen-containing contraceptive use (4% by 5 years off anticoagulation) may be lower than that seen with VTE provoked by other minor risk factors.

? 2021 Thrombosis Canada

Page 3 of 9

PATIENTS WITH AN UNPROVOKED VTE:

Patients with a first episode of unprovoked VTE should receive at least 3 months of anticoagulation, with the decision to continue anticoagulation longer term dependent on the estimated risk of recurrence, the risk of bleeding, and patient preference. In patients with a first unprovoked VTE, the decision to stop anticoagulant therapy or to continue treatment indefinitely is strongly influenced by the preferences of an informed patient. To elicit patient preferences for the purpose of joint decision making, the expected risks of recurrence with and without indefinite anticoagulant therapy and the expected consequences of recurrent VTE and bleeding need to be explained to the patient.

Patients with a first unprovoked episode of proximal DVT or PE, on average, have a risk of recurrence of about 10% in the first year, 25% in the first 5 years and 36% in the first 10 years after stopping anticoagulant therapy. Long-term anticoagulation should be considered for these patients, based on the risks of recurrent VTE and bleeding.

The risk of recurrence after a first unprovoked proximal DVT or PE can be further stratified according to the patient's sex and D-dimer results measured 1 month after stopping anticoagulant therapy:

? men have ~1.5-fold higher risk of recurrence than women (~12% vs. ~8% in the first year after stopping therapy);

? patients with a positive D-dimer versus negative D-dimer have ~2-fold higher risk of recurrence;

? the predictive values of sex and D-dimer results for recurrent VTE are additive: male and Ddimer negative: ~8% in the first year; male and D-dimer positive: ~16% in the first year; female and D-dimer negative: ~5% in the first year; female and D-dimer positive: ~10% in the first year.

Prognostic models:

Three models to predict the risk of recurrent VTE after anticoagulation discontinuation following a first unprovoked DVT or PE have undergone external validation (e.g., in a patient population or data set separate from which they were derived). However, each have significant limitations as discussed below, which limit broad applicability.

1) HERDOO2

PREDICTORS OF RECURRENCE

RULE

? Hyperpigmentation, edema or ? Female patients with 250 ug/L during

and may consider anticoagulant discontinuation

anticoagulation

? Women with >2 predictors of recurrence and all

? Body mass index (BMI) >30 kg/m2

men are classified as high risk of recurrence

? Age >65 years

? 2021 Thrombosis Canada

Page 4 of 9

Unlike other investigators, the HERDOO2 investigators classified unprovoked VTE as all VTE (including estrogen- and pregnancy-related) not occurring in the setting of a major reversible provoking risk factor or cancer. As such, the risk of recurrence in women with less than 2 predictors of recurrence in this model is likely to be higher in those who are older. In low risk women under 50 years of age who discontinued anticoagulants, the risk of recurrent VTE was low regardless of whether their initial event was estrogen associated. However, in women 50 years of age or older with less than 2 predictors of recurrence who stopped anticoagulants, the risk of recurrence was 5.7% per patient year. Therefore, further research is required before this rule can be confidently used in women 50 years of age. A subsequent analysis has shown that the HERDOO2 D-dimer cutpoint (and, therefore, rule) is not valid with D-dimer assays other than the VIDAS D-dimer. It is noteworthy that most patients in the HERDOO2 studies had D-dimer testing on a vitamin K antagonist rather than a DOAC.

2) DASH

PREDICTORS OF RECURRENCE

RULE

? Abnormal D-dimer level after approximately

1 month off anticoagulation (+2 points) ? Male sex (+1 point) ? Age 5% even in those with the lowest DASH score. As with the HERDOO2 rule, further research is needed in older patients.

3) The Vienna prediction model, which includes sex, site of index event and D-dimer, uses a nomogram to calculate risk of recurrence at 1 year and 12 years after anticoagulant discontinuation (risk calculator available at ). Although this model has been validated in a separate pooled data set, its safety and efficacy have not been formally assessed in a clinical impact study in which the results of the model are used to guide patient management decisions.

PATIENTS WITH PERSISTENT RISK FACTORS:

Patients with strong persistent risk factors (active cancer, high risk thrombophilia) should remain on anticoagulation indefinitely if the bleeding risk is acceptable.

a) Persistent risk factors that usually prompt continuation of anticoagulation:

? Active cancer: The risk of recurrent VTE is markedly increased in patients with active cancer (perhaps 20% per patient year, initially) and this risk is higher in patients with metastatic disease (compared with localized disease) and in patients on chemotherapy. The risk of recurrent VTE may be lower if the initial event occurred while patients were

? 2021 Thrombosis Canada

Page 5 of 9

receiving chemotherapy and chemotherapy was subsequently stopped. [See Clinical Guide: Cancer and Thrombosis]

? Antiphospholipid antibody positivity: The presence of persistently positive moderate-tohigh titre antiphospholipid antibodies and/or a lupus anticoagulant and VTE (fitting the criteria for antiphospholipid antibody syndrome) is considered high risk for VTE recurrence (and arterial thrombosis) and these patients should generally receive anticoagulant therapy indefinitely. Consultation with a Thrombosis specialist or Hematologist is suggested. [See Clinical Guide: Thrombophilia: Antiphospholipid Antibody Syndrome]

? High risk hereditary thrombophilia: Given the low prevalence of the higher risk thrombophilias, screening for hereditary thrombophilia is generally not recommended to determine duration of anticoagulation. However, if a patient is known to have antithrombin, protein C or protein S deficiency or is homozygous or compound heterozygous for factor V Leiden or prothrombin G20210A with a history of VTE, the risk of recurrent VTE is higher and the patient may be a candidate for indefinite anticoagulant therapy. Consultation with a Thrombosis specialist or Hematologist is suggested. [See Clinical Guides: Thrombophilia: Deficiencies in Protein C, Protein S, and Antithrombin and Thrombophilia: Factor V Leiden and Prothrombin Gene Mutation]

b) Persistent risk factors that do not usually influence duration of anticoagulation:

? Low risk hereditary thrombophilia and/or family history of VTE: The presence of one of the common hereditary thrombophilia conditions (i.e. heterozygosity for factor V Leiden or prothrombin G20210A) does not appear to be a clinically important risk factor for recurrence of VTE either during or after anticoagulant therapy. A positive family history alone does not increase the risk of recurrent VTE.

? Presence of an inferior vena cava filter: The presence of an inferior vena cava filter (IVF) alone should not influence the duration of anticoagulant therapy beyond the duration of treatment for the VTE that triggered the filter insertion.

? Residual abnormalities on ultrasound: These are detected in approximately one third of patients. Although these findings may increase the likelihood of recurrence after stopping anticoagulants, the associated risk is not sufficient to make this a deciding factor in determining duration of anticoagulant therapy.

PATIENTS WITH A SECOND EPISODE OF VTE

Although a second episode of VTE suggests a higher risk of recurrence, the recommendation for

duration of anticoagulant therapy is dependent on whether the VTE was provoked or unprovoked.

? 2021 Thrombosis Canada

Page 6 of 9

TABLE 4: SUMMARY OF RECOMMENDATIONS FOR DURATION OF TREATMENT

CATEGORIES OF VTE

DURATION OF TREATMENT

First VTE provoked by a transient risk factor 3 months*

Second VTE provoked by a transient risk factor

Same as for first VTE provoked by a transient risk factor*

First unprovoked VTE

Minimum of 3 months and then reassess.

With low or moderate bleeding risk

Indefinite therapy with periodic reviews?

With high bleeding risk

3 months, especially if recurrent VTE risk is relatively lower and/or bleeding risk factors cannot be mitigated

Second unprovoked VTE

Same as for first unprovoked VTE; this is a strong indication for indefinite anticoagulant therapy unless there is a very high bleeding risk?

Isolated distal DVT

3 months*

Central venous catheter(CVC)-associated VTE 3 months*; longer if CVC remains in place

VTE associated with ongoing non-cancerrelated risk factors (e.g. paraplegia or other significant immobility, active inflammatory bowel disease, high risk thrombophilia)

Indefinite therapy with periodic reviews or as long as the risk factor persists?

Cancer-associated VTE

Minimum 3 months, then reassess and continue if active cancer or patient continuing to receive anticancer therapy

* Although 3 months is the usual length of time-limited treatment, 6 months may be preferred if: (i) the DVT or PE was very large or very symptomatic; or (ii) symptoms of the initial DVT or PE persist; or (iii) the patient is not ready (confident enough) to stop anticoagulant therapy at 3 months; and (iv) the patient does not have a high risk for bleeding.

Absence of a transient risk factor, active cancer or other ongoing clinical risk factor for recurrent VTE.

? Patients who have been recommended indefinite anticoagulant therapy should be reassessed periodically (e.g. yearly) to re-estimate the VTE versus bleeding risk balance and review patient preferences.

For patients continuing on long term rivaroxaban (Xarelto?) or apixaban (Eliquis?) beyond 6 months, dose reduction of rivaroxaban to 10 mg once daily or apixaban to 2.5 mg twice daily can be considered based on the results of the EINSTEIN CHOICE and AMPLIFY Extend studies in which these lower doses were as effective and safe as standard dosing.

? 2021 Thrombosis Canada

Page 7 of 9

SPECIAL CONSIDERATIONS:

Pediatrics If possible, pediatric hematologists with experience in thromboembolism should manage children with or at risk for thrombosis, as well as those receiving antithrombotic therapy. When this is not possible, a combination of a neonatologist/pediatrician and an adult hematologist, supported by consultation with an experienced pediatric hematologist, should manage these children.

Central venous catheter (CVC) associated VTE CVC-associated VTE should be treated like a provoked VTE. [See Clinical Guide: Central Venous Catheter-Related Thrombosis].

OTHER RELEVANT THROMBOSIS CANADA CLINICAL GUIDES:

? Apixaban (Eliquis?) ? Cancer and Thrombosis ? Central Venous Catheter-Related Venous Thrombosis ? Deep Vein Thrombosis (DVT): Treatment ? Pregnancy: Venous Thromboembolism Treatment ? Pulmonary Embolism (PE): Treatment ? Rivaroxaban (Xarelto?) ? Thrombophilia: Antiphospholipid Antibody Syndrome ? Thrombophilia: Deficiencies in Protein C, Protein S, and Antithrombin ? Thrombophilia: Factor V Leiden and Prothrombin Gene Mutation

REFERENCES:

Agnelli G, et al. Apixaban for extended treatment of venous thromboembolism. N Engl J Med 2013;21;368(8):699-708.

Carrier M, et al. Systematic review: case-fatality rates of recurrent venous thromboembolism and major bleeding events among patients treated for venous thromboembolism. Ann Intern Med 2010;152(9):578-589.

Eichinger S, et al. Risk assessment of recurrence in patients with unprovoked deep vein thrombosis or pulmonary embolism: the Vienna prediction model. Circulation. 2010;121:1630-1636.

Eischer L, et al. The risk of recurrence in women with venous thromboembolism while using estrogens: a prospective cohort study. J Thromb Haemost 2014;12:635-640.

Ensor J, et al. Systematic review of prognostic models for recurrent venous thromboembolism (VTE) post-treatment of first unprovoked VTE. BMJ Open 2016;6(5):e01190.

Kearon C, et al. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2016;149(2):315-352.

Kearon C, et al. Categorization of patients as having provoked or unprovoked venous thromboembolism: guidance from the SSC of ISTH. J Thromb Haemost 2016:14:1480-1483.

? 2021 Thrombosis Canada

Page 8 of 9

 ................
................

In order to avoid copyright disputes, this page is only a partial summary.

Google Online Preview   Download